1. Technical Field
The present invention relates to an implantable drug delivery pump, a drug reservoir unit, and an implantable drug delivery system. Such pumps, units, or systems may be refilled with the drug, typically by percutaneous drug injections into reservoirs via body tissue.
2. Background Art
Implantable drug delivery systems may be used for systemic or local delivery of drugs. Examples of systemic drug delivery include the regulated infusion of insulin into the body tissues for the treatment of diabetes and the infusion of Apomorphine for the treatment of advanced Parkinson's disease. The local delivery of drugs or therapeutic agents has particular application to the treatment of neurological conditions where the blood brain barrier prevents many systemically administered drugs from reaching the desired target, or where the delivery of drugs or therapeutic agents to targets other than the desired target may produce unacceptable side effects. Examples of local drug delivery into the cerebrospinal fluid that surrounds the spinal cord and brain include the intrathecal delivery of opioids for chronic pain control and the intrathecal delivery of baclofen for the treatment of spasticity. Drugs and therapeutic agents may be also delivered directly into the brain parenchyma via a catheter whose discharge portion lies adjacent to a predetermined target. Examples of this type of therapy include the infusion of gamma-amino-butyric acid agonists into an epileptic focus or pathway that will block its transmission, the delivery of cytotoxic agents directly into a brain tumor, and the infusion of neurotrophic agents for the protection and repair of failing or damaged nerve cells.
Intraparenchymal delivery of neurotrophins may be used to treat a variety of neurodegenerative disorders including Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis, and may be also useful in stimulating the repair of damaged neural tissue after injury from trauma, stroke or inflammation.
Examples of drug delivery pumps are shown, for example, in U.S. Pat. Nos. 4,013,074 and 4,692,147, each of which describe drug filled reservoirs located within the pump, which are positioned within a housing that contains a gas such that when the reservoir is filled, the gas is compressed which in turn, provides the pressure to empty the reservoir. In particular, U.S. Pat. No. 4,692,147 describes a battery powered motor driven pump, which may be seen in FIGS. 1 to 3 of this specification. From FIG. 1, it will be understood that the pump 1 is implanted subcutaneously, and that it may be refilled via a refill port 2, which may be accessed by percutaneous drug injection. The pump 1 includes an outlet port 3 through which the drug is pumped to an outlet tube 4.
Referring to FIG. 2, it will be seen that the pump 1 includes a pump unit 5 beneath which is located a dish 6 which defines a reservoir. The pump unit 5 and the dish 6 are enclosed by top and bottom parts of a housing 7, 8. The pump unit 5 includes the drug refill port 2, batteries 9, and a roller pump 10.
FIG. 3 shows the roller pump 10 in more detail. Within the roller pump 10 is a rotor 11 mounted for rotation within a pump housing 12. The rotor 11 includes two diametrically opposite arms, each of which terminates in a roller 13 which engages with a length of tubing 14 such that, as it rotates, the rollers 13 at the end of the rotor arms crush the length of tubing to drive the fluid through the length of tubing 14 as the rotor 11 rotates from an inlet 15 to an outlet 16. A flexible sheet 17 overlies the length of tubing 14, over which the roller 13 moves, the sheet 17 acting as a shim between the length of tubing 14 and the rollers 13. An example of a pump arranged in a similar way to that described in U.S. Pat. No. 4,692,147 is the Synchromed EL pump (Medtronic Inc, Minneapolis).
Passive drug reservoirs are also known where regulators control the flow of fluid exiting a gas-pressurized drug filled reservoir. The energy required to deliver the drug to its target is imparted to the pump upon filling the reservoir and compressing the gas. The regulators are either coiled lengths of fine bore tubing or etched fluid conducting channels in a chip. Passive drug dispensers are less reliable in delivering the desired dose than mechanical dispensers since the dose of drug delivered by passive dispenser depends upon the pressure in the drug filled reservoir, the resistance set by regulator, the resistance in the pump to catheter tubing, the resistance in the catheter, the pressure applied by the tissue (tissue turgor) at the catheter's delivery port, as well as the viscosity of the fluid being delivered. With passive drug dispensers, the accuracy of drug delivery is least reliable when the flow rates are low and the regulator needs to impart a high resistance. In these circumstances, small changes in the viscosity will have a significant bearing on the flow rate and the dose of drug delivered. For the delivery of neurotrophic factors into the brain parenchyma, low flow rates of the order of 1–10 μl per hour are desirable and because neurotrophic factors are proteins in suspension. They will impart a higher viscosity than crystalloid drugs and alter the flow rate accordingly. Proteins in suspension may also have a tendency to deposit within the fine tubing or etched channels of the passive regulator and further influence the flow rate.
Thus, for the delivery of proteinaceous drugs and particularly the intraparenchymal delivery of neurotrophic factors to the brain, battery powered mechanical dispensers are preferable to passive dispensers. For safety as well as the ability to alter the dosing regimen as required, a pump that can be controlled by telemetry is also desirable. Of the battery powered mechanical pumps described in the prior art that are programmable using telemetry, all have the drug dispenser unit containing the battery or batteries, motor, dispensing actuator and electronics for programming housed with the pressurized drug filled reservoir. This tends to make the pumps bulky for subcutaneous implantation because the reservoir alone may contain between 10 and 24 ml. The Synchromed EL pump contains a reservoir of 16 ml, is cylindrical in shape and has a diameter of 7 cm and a height of 2.9 cm. Its size means that it is necessary to implant such pumps subcutaneously in the anterior abdominal wall where they are least obtrusive. Nevertheless, when implanted in thin patients, the bulk of the pump can cause considerable inconvenience and discomfort. If, on the other hand, the pump is deeply placed in the subcutaneous fat of an obese patient, finding the refill port can be also problematic. Minimizing the volume of the reservoir of the pump has the disadvantage that the pump will require percutaneous refilling more frequently, thereby increasing the necessity for the patient to attend a clinic, and increasing the risk of introducing infection.
To treat neurodegenerative disorders, brain injury or other disorders with neurotrophins, it may be desirable to deliver them to more than one neurological site in the central nervous system, preferably the brain or spinal cord, most preferably the brain. For example, Parkinson's disease may be treated by infusing glial-derived neurotrophic factor (GDNF) delivered by one or more catheters implanted bilaterally into each dorsal putamen. Similarly, Alzheimer's disease may be treated by infusing nerve growth factor delivered by one or more catheters implanted bilaterally into each nucleus basalis.
Delivering the drug to multiple sites by implanting multiple pumps of the types described in the prior art would be unacceptable, and only U.S. Pat. No. 5,752,930 discloses the delivery of a drug from a single pump to multiple sites. This teaches the fluid delivery through a single catheter with multiple ports. Such a device will not facilitate drug infusion bilaterally into the brain or to other sites other than those along the axis of the implanted catheter.
Each of the prior art documents referred to above are herein incorporated in their entirety by this reference.
Two or more catheters could be connected to the outflow tubing from a single pump via a single input/multiple output connector. Such an arrangement would not guarantee an even distribution of drug to each catheter because fluid will flow primarily down the catheter offering the least resistance. To overcome this, the connector would have to act as a regulator to ensure that resistance is overcome. This will put a great demand on the pump and will increase the stress on joints between the pump and the connector. For very low flow rates, such as one or two μl per hour, the outflow ports in such a connector acting as a regulator will need to be extremely small.